Although numerous clinically used drugs derive from plant natural products, little is known about their biosynthetic genes, limiting the understanding of plant metabolism and preventing access to engineered hosts for their production (de Luca et al, 2012). In spite of the promise of genomics and synthetic biology, few plant biosynthetic pathways have been elucidated so far. Of those, only three have been successfully transferred to a heterologous host for current or future industrial production, namely artemisinic acid (Paddon et al., 2013), the benzylisoquinoline alkaloids (Thodey et al., 2014, DeLoache et al., 2015), and the monoterpenoid indole alkaloids, aka MIA (Brown et al., 2015; Qu et al., 2015). The paucity of information regarding plant biosynthesis is especially stark in comparison to the >700 bacterial and fungal natural product biosynthetic pathways that have been characterized so far (Cimermancic et al., 2014).
Podophyllotoxin, a lignan from the endangered medicinal plant Himalayan Mayapple (Podophyllum hexandrum), is a known precursor to the antineoplastic compound etoposide (Stahelin et al., 1991; Canel et al., 2000; Gordaliza et al., 2004). Although etoposide is on the World Health Organization's list of essential medicines, the only route for its production involves the isolation of (−)-podophyllotoxin from the Mayapple plant (Lata et al., 2009) and its subsequent multistep, semisynthetic conversion to etoposide. Each of these steps is required for its potent topoisomerase inhibitory activity, which is not present in podophyllotoxin.
Knowledge of a biosynthetic route would enable more facile access to etoposide, and potentially to natural and unnatural derivatives that would be difficult to produce synthetically.
It would be highly desirable to have a simplified and more direct route to etoposide and etoposide intermediaries that circumvents the need not only for the Mayapple cultivation, but also for the semisynthetic epimerization as well as demethylation that are currently required for production.